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Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.

The concept of cellular brain repair for Parkinson's disease is relatively simple - if brain cells die in this condition, then it should be possible to replace these cells through transplantation of healthy cells back into the brain. Over the past three decades, numerous animal studies and several clinical trials in human patients have shown that this concept has significant potential for repairing the brain affected by Parkinson's disease. However, poor survival of the healthy cells has limited the widespread roll-out of this cellular reparative approach to patients. Biomaterials, that is, materials that have been engineered to interact safety with living tissue for therapeutic purposes, have the potential to improve such cellular reparative therapies for Parkinson's disease. Specifically, injectable biomaterials gels have the potential to significantly improve cell survival by providing a physical scaffold and pro-survival environment for the implanted cells. Thus the aim of this proposal is to determine if biomaterial hydrogels can be used to improve cellular reparative therapies for Parkinson’s disease using animal models of the condition. We will specifically investigate the beneficial effect of biomaterials on stem cell-derived neuron cell transplantation approaches.

The proposed research uses standard molecular biology, protein purification and biophysical structural analysis methods in a focused series of experiments that comprise a complete 6-week project. This builds on existing molecular genetics studies that have identified novel missense mutations in KMT2D (also known as MLL2) as the cause of a unique phenotype (renal tubular dysgenesis, choanal atresia and athelia). Previous studies have identified KMT2D mutations as a major cause of Kabuki syndrome, a comparatively common autosomal dominant congenital mental retardation syndrome. The missense mutations occur in a central region of the KMT2D protein (2841-3876) that does not have variants associated with Kabuki syndrome. This central region contains a series of coiled-coil domains that are likely to mediate protein-protein interactions. However, the effect of the missense mutations on KMT2D structure and interactions is completely unknown. This project will determine the structure-function relationships between KMT2D and a unique phenotype that are likely to be caused by altered protein-protein interactions, as well as describing the broader genotype-phenotype correlations in this important gene. The approach described in the proposal is the only tractable way to understand possible structure-function relationships, given the large size of the gene and encoded protein.

Timely reperfusion of the occluded cerebral vasculature can minimize brain damage and optimize positive patient outcome. Current therapeutic approaches include administration of tissue plasminogen activator to dissolve an occlusive clot pharmacologically. More recently, mechanical clot removal devices are becoming a favoured approach. However, reperfusion injury can develop and haemorrhagic transformation (HT) of recently ischaemic brain is a potentially fatal complication of thrombolytic and mechanical reperfusion therapy. MMP-9 and MMP-2 expression in brain tissue is indicative of disruption of the blood brain barrier [3]. Heightened MMP-2 is associated with more favourable outcomes than MMP-9; high expression of MMP-9 is associated with haemorrhagic transformation and poorer clinical outcomes [4, 5]. Specific objectives during summer placement: - To experience real science by integrating into a research team. - To learn and master the techniques implicit in immunohistochemistry and other histological measures, including tissue slicing, antibody staining and quantitative assessment of biomarkers. - To contribute to the on-going assessment in the host lab, of the impact of varied reperfusion approaches following middle cerebral artery occlusion on the subsequent development of reperfusion injury. In particular, MMP-9 and MMP-2 expression in rat brain will be quantitatively assessed.

Huntington’s disease (HD) is a debilitating, relentlessly fatal neurodegenerative disease. HD is caused by inheritance of an expanded CAG repeat tract in the HTT gene. The CAG repeat continues expanding in the brain of HD patients, and these somatic expansions contribute to disease progression and age of onset. It is known from model systems that the DNA repair protein MutSbeta (Msh2-Msh3 complex) is essential to drive expansions, as knockout of either Msh2 or Msh3 blocks nearly all expansions. Recent work from the supervisor’s laboratory suggests that MutSbeta expansion activity is regulated by post-translational acetylation. This link to protein acetylation is noteworthy with regard to potential therapy, in light of the supervisor’s recent demonstration that inhibiting histone deacetylase 3 in HD mice blocked disease onset. Using cultured human cells, I will test potential acetylation control of the Msh2 subunit of MutSbeta by mutating a putative acetylation site, lysine 73, to convert it to the non-acetylatable arginine (Msh2K73R). I will then test Msh2K73R protein expression and its ability to form MutSbeta complex. I will assist in genetic assays to measure CAG repeat expansions in cells expressing Msh2K73R, compared to wild type. My prediction is Msh2K73R will drive expansions in an acetylation-independent manner.

The diffusion of chemokines in the extracellular matrix is a requirement for the formation of chemokine gradients that guide immune cell migration to sites of inflammation, and controlled by matrix glycans of the glycosaminoglycan family. The focus of this research is to use well-defined models of the extracellular matrix to probe the interaction between the chemokine CXCL12 and the glycosaminoglycan heparan sulphate, and how this defines the mobility of CXCL12. The first key goal of the project is to design and produce a fluorescently-tagged CXCL12 mutant with modulated glycosaminoglycan binding which can be compared against the wild-type chemokine and other mutants already available. The second key goal is to use the biophysical method of fluorescence recovery after photobleaching to characterise the differential diffusion of mutant and wild-type CXCL12 in glycosaminoglycan-rich matrices. This project thus combines biochemistry and biophysics to gain a better understanding of the molecular mechanisms underpinning the formation of chemokine gradients in extracellular matrix.

The primary goal of this study is to assess the feasibility and acceptability of using the Diabetes Medication Choice Decision Aid in decisions about medication intensification in an Irish setting using a mixed methods approach. The extent to which patients are involved in the decision-making process about medication intensification will be measured using a validated tool (OPTION) in audio-taped consultations where the decision aid is used and not used. Health care professionals and patients will also be interviewed about how useful they found the decision-aid in involving patients in decisions about changes to medication.The quantitative analysis of the consultations will allow us to assess the level of patient involvement in the decision-making process around medication intensification. The qualitative interviews will provide us with a greater understanding of how useful the decision-making tool is in facilitating shared decision-making. The findings from this feasibility study will inform a future pilot randomised controlled trial of the decision aid in people with type 2 diabetes requiring medication intensification.

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

The aim of this project will be to determine the angiogenic potential of plasma-coated graphene oxide sheets and their effect on cell viability. The objectives will be to place human umbilical cord endothelial cells(HUVECs) in Matrigel with graphene oxides with varying surface coatings on the graphene oxide. First we will use a plasma reactor to modify the surface properties by increasing the O2 and N2 groups on the surface. HUVECs will then be cultured using EGM-2 complete media before being placed onto Matrigel, along with surface treated graphene oxide. In order to determine the cytotoxic effect of each coating, a Live/Dead assay will be carried out on HUVECs that have been cultured in the presence of plasma-treated graphene oxide sheets after a 48hr culture, using fluorescent detection, while the angiogenic properties of each surface coating will be compared against an uncoated control, with complete media with growth factors being used as a positive control, using ImageJ software which will quantify the number/density and size of the vessels compared to the uncoated control. The ideal result would be a coating that has strong angiogenic properties with minimal cytotoxic properties, which would set the ground work for further in-vitro studies.

We will be investigating the viability of using cyanobacteria as a model for our own by exploring the evolutionary links as well as the similarities between human cells and cyanobacteria cells in terms of the communication and cell differentiation. This will allow us to use the cyanobacteria as a model for human stem cells. There are 3 cases which will be investigated: metabolism of retinoic acid, nitrogen-fixing cells and prostaglandin cell signalling. In each case, we will be blocking the signal, modifying the bacteria and studying how this affects the bacteria. The production of proteins and the chemical signalling are amongst the several responses we will be monitoring. Using information gained from this we will be able to see if there is a viable link that can be used to monitor cyanobacteria that have human orthologues spliced into it.

Palliative medicine deal with a fragile population- both in terms of the patient themselves and their families. Psychological health is often an extremely delicate topic to approach. By conducting a comparative study across different settings – home, hospice and hospital I intend to begin bridging that gap between physical and psychological care. I will conduct a cohort study to gather qualitative data on the mental wellbeing of palliative care patients, specifically measures of depression, anxiety and quality of life. Examining the relationship between symptoms depression, anxiety and adjustment disorder in a palliative population will allow terminally ill patients the opportunity to be heard. Publishing my data and statical findings introduces the possibility that end-of-life patients could improve their peers treatment and quality of life. Furthermore, by uncovering an intricate connection between a palliative patient's environment and their overall wellbeing, my research could help to produce local and national guidelines for a more tailored healthcare plan.

Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.

Schizophrenia desperately needs new drugs. It affects 1% of adults, is a global health problem yet medications are only partially effective. They reduce psychotic symptoms but not negative symptoms and cognitive deficits, which are key factors for explaining illness-related disability. Schizophrenia and cognition are complex but highly heritable so genetics represents a vital tool for understanding neurobiology in the absence of biomarkers. A network of 150 coexpressed genes has been identified that is conserved throughout the human cortex. It is enriched for rare and common genetic variants associated with cognitive phenotypes and neuropsychiatric disorders. I plan to use the newest/largest available genetic studies of schizophrenia and cognition ( > 380,000 individuals) to study this gene network in these phenotypes. I will use gene-set analysis to test the network for enrichment of genes associated with schizophrenia or cognition. I will quantify the proportion of SNP-based heritability for schizophrenia or cognition that can be attributed to genes in this network. I will investigate what individual genes are associated with either phenotype or with both, i.e. genes that are having a pleiotropic effect. This can point to the biological processes that underlie cognitive deficits in schizophrenia and be a foundation for new methods of treatment.

Obesity causes brain insulin resistance and prevents the brain from regulating metabolic responses, maintaining energy balance and controlling the nutritional status of an individual. Restoring the brain’s ability to modulate metabolic functions could be an important intervention to prevent the negative outcomes of obesity and diabetes. The Dorsal Vagal Complex (DVC) in the brainstem senses insulin to regulate glucose metabolism, food intake and body weight in rodents. Three days of high-fat diet feeding is sufficient to completely disrupt the insulin response in the DVC, thus causing an increase in blood glucose levels and excessive eating. Recently, I discovered that increased mitochondria fission and ER stress in the DVC can cause insulin resistance and affect the ability of the DVC to regulate blood glucose levels. I aim to understand whether increased mitochondria fission in the DVC can affect food intake and body weight in rats. Using in vivo and in vitro experiments, I aim to uncover the mechanism by which changes in mitochondria shape and size affect DVC insulin sensing and eating habits in rodents. This project could lead the way for the development of novel approaches that target the brain to regulate food intake and body weight in obese subjects.

Peripheral nerves are responsible for haptic, somatic and visceral sensations including that of pain. Healthy nerves conduct action potentials from their peripheral endings to the dorsal spinal cord, where synaptic transmission first takes place. It is assumed that the peripheral somatosensory signals are first integrated in the spinal cord and subsequently analysed in the brain. Our recent findings has challenged this view and suggested that peripheral somatosensory ganglia (such as dorsal root ganglia, DRG) are capable to regulate pain transmission utilising GABAergic somatic cross-talk mechanisms. I hypothesize that somatosensory ganglia represent a new type of a ‘gate’ within the somatosensory system. My overarching goal is to develop a comprehensive mechanistic understanding of the peripheral somatosensory gating. I will use in vivo electrophysiology, mouse transgenics, chemo- and optogenetics, behavioural models and other cutting-edge approaches to address the following specific aims. (1) Secure direct in vivo evidence for peripheral somatosensory integration at the DRG. (2) Moving beyond GABA: identify other major ganglionic communication mechanisms. (3) Elucidate physiological context of signal integration in the DRG. (4) Identify subcellular structures involved in somatic integration. These studies will change current understanding of somatosensory processing and will provide new ideas for pain treatment at the periphery.

Oesophageal adenocarinoma (OAC) is a type of cancer affecting the lower part of the oesophagus (the gullet). The number of patients diagnosed with OAC has increased substantially over the past three decades. As a result, OAC is now the most common type of cancer affecting the oesophagus. Unfortunately, there are currently few effective treatments for OAC. Many patients with OAC will however first be diagnosed with Barrett's oesophagus. This is a condition in which the normal lining of the lower oesophagus becomes glandular and starts to grow abnormally. It is not clear why this happens but it may be related to reflux of stomach contents (such acid and bile) into the oesophagus (as happens in patients who frequently experience heartburn). Our research suggests that bile and acid may be able to change the concentrations of proteins within the glandular cells. The altered levels of these proteins may then contribute to the cells becoming cancerous. This work will look to see if this is the case and ma help us to find new drug targets to prevent and treat Barrett's and OAC.

Despite success in in-vitro and in pre-clinical models, the therapeutic efficacy of mesenchymal stem or stromal cells (MSCs) is somewhat limited. In this project, we will investigate two different strategies to enhance their therapeutic efficacy by forced expression of Programmed Death-Ligand1. PD-L1 expression has been shown to protect cells and tissues from T-Cell mediated cell death. Recent work carried out by Prof.Ritter’s lab showed that overexpression of PD-L1 on corneal tissue before transplantation significantly prolongs corneal allograft survival upon transplantation in allogeneic recipients. This indicates a pivotal role for PD-L1 in immunomodulation. Additionally and as of interest, preliminary data indicate that expression of PD-L1 is highly up-regulated on licensed MSCs or on MSC treated with tumor conditioned medium (TCM) indicating a role in immune evasion of tumors. We aim to understand if forced expression of PD-L1 enhances the immunoregulatory properties of these MSCs in vitro. We will attempt to achieve this using either lentiviral gene transfer of PD-L1 or licensing with tumor-conditioned medium. This research will contribute significant data to the development of novel treatment protocols for patients suffering from inflammatory conditions such as impaired wound healing in diabetes and ocular surface injuries.

The first carpometacarpal joint, also known as trapeziometacarpal (TMC) joint is considered one of the most important in joint human body. It's articulated in such a way that in provide a whole range of movement that allow the hand to perform task with great dexterity. However, it is also a very vulnerable joint that will be likely affected on individuals with osteoarthritis, especially in women. To amend the underlying problem, prosthetic material can be made and replace the faulty cartilage during surgery to regain function of thumb. However, the estimated size of the prosthetic material is fairly difficult to customize because cartilage will not show up in normal X-ray, hence the estimate size of prosthetic material cannot be made in advance. This study will also to examine if there is a consistency in size and the pattern of degradation of cartilage in persons who had suffered from osteoarthritis (OA) of this joint. Ultimately, information from this study and other ongoing work will inform the structure and design of joint prostheses, with the particular goal of producing individually customised prostheses by 3D printing

Extracellular vesicles(EVs) are tiny vesicles that shuttle genetic information between cells, and throughout the circulation. MicroRNAs(miRNAs) are small non-coding RNAs that regulate gene expression. This study will focus on EV-encapsulated microRNAs(EVmiRs). The host group recently published work showing a potent tumor suppressor role for miRNA-379 in breast cancer. Tumour-targeted delivery of the miR was achieved by harnessing the natural homing capacity of Mesenchymal Stem Cells(MSCs) engineered to over-express miR-379. The MSCs were found to release miR-379 in EVs, and the miR-379 enriched EVs were shown to reduce breast cancer growth in vivo. This study was performed in immunocompromised animals and must be expanded to take the host immune system into account. This will be achieved using murine 4T1 breast cancer cells in immune competent animals. It is necessary to first establish the characteristics of EVs released from these cells. The aim of this study is to define the EV-miR profile of 4T1 cells in vitro. The data generated will inform a subsequent In Vivo study, where EVmiRs detected in vitro will be compared to those detected in the bloodstream of mice bearing 4T1 tumours. This will provide a potential biomarker of disease progression or response to MSC-EV therapy.